Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-29
2002-06-04
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S056000
Reexamination Certificate
active
06399788
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing benzothiophenecarboxamide derivatives useful as prostaglandin D
2
(hereinafter, referred to as “PGD
2
”) antagonists.
BACKGROUND ART
Benzothiphenecarboxamide derivatives of the general formula (I):
wherein R is hydrogen or a hydroxy-protecting group, X is hydrogen or alkyl, and double bond represents E or Z configuration are PGD
2
antagonists specific to PGD
2
receptors and useful as therapeutic agents for treating diseases associated with the dysfunction of the mast cell caused by excessive production of PGD
2
(WO97/00853, PCT/JP97/04527(WO98/25919)). Consequently, the compound of the formula described above may be used as therapeutic agents for systemic mastocytosis, disorder of systemic mast cell activation, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, inflammation, and atopic dermatis. Among them, a compound wherein OR is 5-hydroxy, X is hydrogen and double bond represents Z-configuration (hereinafter, referred to as “Compound A”) possesses high antagonistic effect on PGD
2
, showing especially high anti-nasal occlusion activity, and is contemplated to be a promising drug for treating nasal occlusion.
DISCLOSURE OF THE INVENTION
The compound (I) and processes for preparing the same have been known in literatures (WO97/00853, PCT/JP97/04527 (WO98/25919)). However, the known processes are not necessarily suited for industrial production in terms of production efficiency, safety for workers and environment and efficient use of resources because of the reasons exemplified as follows:
1) it uses silica gel chromatography unsuitable for mass production;
2) it is of low yield and time-consuming;
3) it involves complicated separation and purification processes of the reaction product;
4) it is accompanied by the generation of harmful gas, odor and/or waste fluid; and/or
5) it requires materials harmful or hard to handle as starting compounds, reagents, and/or solvents.
The present invention provides a process for preparing a compound of the formula (I):
wherein R is hydrogen or a hydroxy-protecting group; X is hydrogen or alkyl; and double bond represents either E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises reacting an amino alcohol of the formula (II):
or a salt thereof with a compound of the formula (III):
wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof to yield a compound of the formula (I-2):
wherein R is as defined above; oxidizing the compound (I-2) with halo oxoacid in the presence of a compound of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3):
wherein R is as defined above; reacting the compound (I-3) with an ylide under the conditions for Wittig reaction and, if desired, deprotecting the reaction product.
THE BEST EMBODIMENT FOR PRACTICING THE INVENTION
In a preferred embodiment of the present invention, a compound of the formula (I-2):
wherein R is as defined above is oxidized with halo oxoacid in the presence of 2, 2, 6, 6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3):
wherein R is as defined above.
In another preferred embodiment, a compound of the formula (II-2):
wherein R
2
is alkyl and R
3
is hydrogen or alkyl is reduced with reducing agent-Lewis acid system to yield an amino alcohol of the formula (II) or a salt thereof.
Preferably, the reducing agent used is selected from the group consisting of alkaline metal- or alkaline earth metal-substituted borohydrides; and the Lewis acid is selected from the group consisting of halide of tin, aluminum, titanium, boron, zirconium or nickel and complexes thereof with ethers.
In another preferred embodiment, a compound of the formula (II-2):
wherein R
2
and R
3
are as defined above is converted into an alcohol of the formula (II-3):
wherein R
3
is as defined above; and the alcohol is reduced with a reducing system of metal sodium-alcohol or reducing agent-Lewis acid to provide an amino alcohol of the formula (II) or a salt thereof.
The terms used herein are defined below.
The term “hydroxy-protecting group” means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
The term “alkyl” means C
1
-C
20
linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl, and C
1
-C
6
alkyl is preferred. As alkyl for R
2
, C
1
-C
3
alkyl is preferred.
The term “alkoxy” means C
1
-C
6
linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C
1
-C
3
alkoxy is preferred.
The term “alkoxyalkyl” means alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like.
The term “acyl” means C
1
-C
11
acyl derived from aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like.
The term “aryl” means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, aryl may be substituted by the following substituents.
Examples of substituent include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, carboxy, cyano, sulfonyl, amino, lower alkylamino such as methylamino, dimethylamino, ethylmethylamino or diethylamino, and the like. The aryl group may have one or more substituents at any possible positions. Specific examples of aryl include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like.
The aryl group in the “aralkyl”, “arylsulfonyl”, “aryloxycarbonyl” or “aralkyloxycarbonyl” described below may have similar substituents as defined above.
The term “aralkyl” means an alkyl group substituted by aryl group, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.
The term “alkylsulfonyl” means a sulfonyl group substituted by alkyl group, and includes methanesulfonyl, ethanesulfonyl and the like.
The term “arylsulfonyl” means a sulfonyl group substituted by aryl group, and includes benzenesulfonyl, p-toluenesulfonyl, and the like.
The term “alkyl-substituted silyl” means mono-, di- or tri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl, trimethylsilyl, t-butyldimethylsilyl, and the like.
The term “alkoxycarbonyl” means methoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and the like.
The term “aryloxycarbonyl” means phenoxycarbonyl, and the like.
The term “aralkyloxycarbonyl” means benzyloxycarbonyl, and the like.
As hydroxy-protecting group represented by R, the above-mentioned alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl are preferred and aryl sulfonyl is more preferred.
Examples of salts of a compound of the general formula (I) include alkali metal salts such as lithium salt, sodium salt or pota
Hiramatsu Yoshiharu
Honma Tsunetoshi
Kakinuma Makoto
Okada Tetsuo
Shionogi & Co. Ltd.
Solola T. A.
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